The nonapeptide bradykinin (BK) and the physiologically-related decapeptide kallidin (KD) are endogenous vasoactive peptides generated as short-lived components of the kallikrein-kinin system. They play a key role in the regulation of normal physiological processes in the peripheral (PNS) and central (CNS) nervous systems and are effectors of a number of inflammatory responses, including bronchoconstrition, plasma extravasation, release of prostaglandins and leukotrienes, smooth muscle contraction and relaxation and nociception [Austin C. E. et al., J. Biol. Chem. (1997) 272, 11420-11425; Hess J. F. et al. Biochem. Biophys. Res. Commun. (1992) 184, 260-268]. Under pathophysiological conditions, elevated levels of kinins are rapidly produced from the circulating precursors kininogens by enzymatic action of trypsine-like serine proteases, kallikrein and tissue kallikrein.
Kinins exert their action interacting with two cell surface receptors, Bradykinin B1 receptor (BKB1R) and Bradykinin B2 receptor (BKB2R), belonging to the 7TM-GPCR superfamily.
BKB2Rs are constitutively expressed in most cells and tissue types and mediate the most of acute effects due to BK and KD after their production in plasma and tissues, respectively. BKB1Rs are poorly constitutively expressed under physiological conditions and are induced following inflammatory insults or noxious stimuli, although recent data show the presence of constitutive BKB1Rs in rat and mouse CNS, making BKB1R a particularly attractive drug target.
Overproduction of kinins under pathophysiological conditions is implicated in the pathogenesis of a number of clinically-relevant disorders, including pain, inflammation, hypotension, asthma, colitis, rhinitis, pancreatitis, sepsis and rheumatoid arthritis [Leeb-Lundberg L. M. F. et al., Pharmacol. Rev. (2005) 57, 57, 27-77]. BK is also implicated in peripheral inflammatory processes associated with Alzheimer's disease [Huang H. M. et al., J. Neurochem. (1995) 64, 761-766] and Yong Y. I et al in the growth of several solid tumors [Stewart J. M. Curr. Pharm. Design (2003) 9, 2036-2042]. The role of kinins, specifically BK, in pain and inflammation has been well documented [Marceau F. et al. Nat. Rev. Drug Discov. (2004) 3, 845-852] and has provided impetus to the development of potent and selective BK antagonists. BKB1R is an attractive target to treat inflammation, because it is absent in normal tissues in most systems, but it is inducible following tissue injury under the control of inflammatory cytokines, mitogen-activated protein kinase (MAPK) pathways and some transcription factors such as nuclear factor B (NF-B). BKB1R is more resistant than BKB2R to desensitization [Marceau F. et al. Pharmacol. Rev. (1998) 50, 357-386] making BKB1R antagonism more adapted to chronic or persistent inflammatory systems than BKB2R antagonism. Moreover, kinins have been demonstrated to exert a cardioprotective role which is mediated by BKB2Rs [Heitsch H. Expert Opin. Investig. Drugs (2003) 12, 759-770] as evidenced by BKB2R agonists in alleviating congestive heart failure, hypertension and ischemic heart disease which raises concerns on the clinical use of BKB2R antagonists.
On this basis, several research programs have been initiated for the identification of novel non-peptide ligands binding BKB1 receptors replacing classical peptide antagonists. In recent years these efforts have been heightened with the expectation that useful therapeutic agents with anti-inflammatory properties would provide relief from diseases mediated by a BK receptor pathway [Bock M. G. et al. Current Opinion in Chem. Biol. (2000) 4, 401-406]. The non-peptide BKB1R antagonists that have appeared in the literature since the year 2000 and several of the disclosed structures, generated by different laboratories and belonging to different chemical classes, all share the pharmacophore group “RN—SO2-phenyl” [Marceau F. TRENDS Pharmacol. Sc. (2005) 26, 116-118] that has allowed to derive a hypothesis of docking to the human BKB1 receptor and suggests structural commonalities and a preferential molecular mode of action within the selected compounds.
In the last few years, several classes of non-peptide BKB1R antagonists have been disclosed. Three main classes have been claimed by several pharmaceutical companies:                1) N-(Arylsulfonyl)aminoacid derivatives [Sanofi WO9725315 (1997); Novartis WO 00075107 (2000) and WO02092556 (2002); Bayer AG WO03007958 (20039; Elan Pharmaceuticals WO03093245 (2003); Lab. Fournier SA FR2840897 (2003); Merck & Co. INC. WO2004/054584 (2004)];        2) Biaryl derivatives [Pharmacopeia Inc. WO0105783 (2001); Merck & Co. INC. US2004034064 (2004), US2004029920 (2004), US 2004063761 (2004)];        3) Benzodiazepine derivatives [Merck & Co. INC. WO02099388 (2002)].        4) Dihydropyridine derivatives as Bradykinin Antagonists [Pfizer Inc. WO96/06082].        5) Sulfonylquinoxalone derivatives [US 2006/0293332].        
Nevertheless, it is necessary to find new classes of bradykinin receptor B1 antagonist, because of their high therapeutic potential.
The present inventors have identified a novel class of compounds acting as selective BKB1R antagonists.